The biodefense agent Staphylococcus aureus enterotoxin is regarded as a superantigen (SAg) because it is not processed as conventional peptide and is an incredibly powerful T cell stimulant. Intentional aerosol exposure of S. aureus enterotoxin has the potential to incapacitate large groups of people in enclosed structures with the consequences of such an attack leading to severe respiratory illness in all individuals exposed. Notwithstanding, certain pulmonary diseases in human patients have recently been associated with the presence of SAg, and stimulation of T cells with SAg in the respiratory tract drives an inflammatory cascade resulting in severe pathological outcomes in the lung. Although this pathogenic response is T cell dependent, the individual contributions of CD4 or CDST cells is unknown. Aim 1 will uncover the pathogenic contribution that each T cell subset is responsible for after S. aureus enterotoxin inhalation. Secondly, we will examine a role for the key cytokine IFN-g during the induction of lung injury, by testing if T cell-derived IFN-g is essential for the induction of disease. In Aim 2 we will test our hypothesis that T cell stimulation induces assembly of a pulmonary inflammasome resulting in production of IL-18 and other caspase-1 dependent cytokines. We predict that the receptor pathways of these cytokines trigger pulmonary inflammation that causes aspects of alveolar pathogenesis. Lastly, an emerging clinical scenario will be modeled in Aim 3. While asthma in people is a serious condition that can in some instances result in death, the natural or deliberate overlay of an airway exposure to S. aureus enterotoxin is predicted to be catastrophic. Aim 3 will model this scenario by testing how S. aureus enterotoxin inhalation affects mice undergoing allergic airway disease. The sensitivity of these mice to S. aureus enterotoxin exposure and a role for a T cell triggered inflammatory cascade will be tested. Our hypothesis is that the SAg T cell cytokine response will modulate the allergenic T cells and enhance their migration into the airways. This effect may portend a syndrome similar to that observed in status asthmaticus. In sum, this project of the UCONN Biodefense Program Project grant will explore a medically relevant model by discovering the mechanisms underlying SAg mediated pulmonary inflammation. RELEVANCE (See instructions):